MUC1 PARALLEL CAR (pCAR) THERAPEUTIC AGENTS

Abstract

Provided herein are immunoresponsive cells expressing a MUC1 targeting pCAR comprising a second generation chimeric antigen receptor (CAR) and a chimeric co-stimulatory receptor (CCR). Also provided herein are methods of preparing the immunoresponsive cells and methods of directing T cell mediated immune response using the immunoresponsive cells.

Description

BACKGROUND[0001]Chimeric antigen receptors (CARs), which are at times referred to as artificial T cell receptors, chimeric T cell receptors (cTCR), or chimeric immunoreceptors, are engineered receptors now well known in the art. They are used primarily to transform immune effector cells, in particular T cells, to provide those cells with a desired engineered specificity. Adoptive cell therapies using CAR-T cells are particularly under investigation in the field of cancer therapy. In these therapies, T cells are removed from a patient and modified so that they express CARs specific to the antigens found in a particular form of cancer. The CAR-T cells, which can then recognize and kill the cancer cells, are reintroduced into the patient.[0002]First generation CARs provide a TCR-like signal, most commonly using a CD3 zeta (z) intracellular signaling domain, and thereby elicit tumoricidal functions. However, the engagement of CD3z-chain fusion receptors may not suffice to elicit substan...

AI Technical Summary

Benefits of technology

[0008]The applicants have found that effective T cell responses may be generated using a combination of constructs in which multiple co-stimulatory regions are arranged in distinct constructs. In particular, provided herein are effective pCAR-T cells having parallel CAR (pCAR) constructs that bind to one or more antigens present on a target cell. In some embodiments, the pCAR constructs comprise a CAR (chimeric antigen receptor) comprising a binding element that specifically binds to an epitope found in MUC1 on a target cell and a CCR (chimeric costimulatory receptor) that binds to a distinct epitope found on a target antigen that is also expressed on the target cell. Experimental data provided herein demonstrate that the pCAR-T cells targeting MUC1 can be effective in treatment of cancer.

Problems solved by technology

However, the engagement of CD3z-chain fusion receptors may not suffice to elicit substantial IL-2 secretion and / or T cell proliferation in the absence of a concomitant co-stimulatory signal.

In general, however, the results achieved with these third generation CARs have been disappointing, showing only a marginal improvement over 2nd generation configurations, with some third generation CARs being inferior to 2nd generation configurations.

These properties of pCAR-T cells make them attractive candidates for treatment of solid tumors, where 1st, 2nd and 3rd generation CAR-T cells show limited efficacy in part due to T cell exhaustion.

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